I. Field of the Invention
The present invention relates to the fields of oncology, genetics and molecular biology. More particular the invention relates to the identification, on human chromosome 1, of a tumor suppressor gene. Defects in this gene are associated with the development of cancer.
II. Related Art
Oncogenesis was described as a multistep biological process, which is presently known to occur by the accumulation of genetic damage. On a molecular level, the multistep process of tumorigenesis involves the disruption of both positive and negative regulatory effectors (Weinberg, 1989). The molecular basis for human colon carcinomas has been postulated, by Vogelstein and coworkers (1990), to involve a number of oncogenes, tumor suppressor genes and repair genes. Similarly, defects leading to the development of retinoblastoma have been linked to another tumor suppressor gene (Lee et al., 1987). Still other oncogenes and tumor suppressors have been identified in a variety of other malignancies. Unfortunately, there remains an inadequate number of treatable cancers, and the effects of cancer are catastrophic—over half a million deaths per year in the United States alone.
Cytogenetic aberrations, as well as high frequency loss of heterozygosity (LOH), have been observed within the short arm of human chromosome 1 (Bomme et al., 1994; Bieche et al., 1994; Kovacs et al., 1988; Bieche et al., 1998). In a cytogenetic analysis of colorectal adenomas, the most common chromosome involved in structural aberrations was chromosome 1. Breakpoints clustered within chromosome 1p32–p36 (Bomme et al., 1994). These data suggest that chromosome 1p loss is an early event in colorectal tumorigenesis. At least three separate regions of LOH have been consistently documented with chromosome 1p (1p22–1p31, 1p34–1p35 and 1p36). In a variety of histologically diverse human tumors, including breast, colon and neuroblastoma (Bomme et al., 1994; Bieche et al., 1994; Kovacs et al., 1988; Bieche et al., 1998; Lo Cunsolo et al., 1999). LOH in familial breast cancer indicated common regions of loss that included 1p36 (32%) and 1p32 (51%) (Millikan et al., 1999).
A recent report investigated LOH in a variety of solid tumors and found high frequency LOH in stomach, colon and rectum, breast, endometrium, ovary, testis, kidney, thyroid and sarcomas (Ragnarsson et al., 1999). In addition, several studies have shown that deletions in the 1p36 and 1p32 region correlated with poor survival in colon and breast cancers (Borg et al, 1992; Ogunbiyi et al, 1997; Tsukamato et al, 1998). Functional studies using microcell fusion have also mapped a tumor suppressor locus in colon cancer to within chromosome 1p36 (Tanaka et al., 1993). Candidate tumor suppressor genes p73 and Rad54 have been mapped to 1p36 and 1p32, respectively. However, expression studies and mutational analyses have failed to suggest their importance in colon and breast cancers (Han et al., 1999; Ichimiya et al, 1999; Rasio et al, 1997). Thus these data suggest that an important tumor suppressor gene or genes resides within chromosome 1p32–1p36 and is involved at high frequency in a number of histologically diverse human cancers.
Despite all of this information, the identity of the gene or genes involved with chromosome 1 LOH remains elusive. Without identification of a specific gene and deduction of the protein for which it codes, it is impossible to begin developing an effective therapy targeting this product. Thus, it is an important goal to isolate the tumor suppressor(s) located in this region and determine its structure and function.